Researchers at Gladstone Institutes announced on Apr. 3 that they have identified a sequence of molecular events that may explain early brain activity changes in people carrying the APOE4 gene, which is known to be the strongest genetic risk factor for Alzheimer's disease. The findings, published in Nature Aging, were based on studies conducted in mouse models and suggest a possible path for new treatments.
The study matters because APOE4 is present in about one quarter of the population and found in an estimated 60 to 75 percent of all patients with Alzheimer's disease. Understanding how this gene variant leads to cognitive decline could help develop therapies that intervene before memory problems arise.
The research team discovered that APOE4 increases production of the protein Nell2, causing neurons to shrink and become hyperactive at an early age. This neuronal hyperactivity was linked with more severe memory issues later in life. When researchers reduced Nell2 levels, even adult mice carrying APOE4 showed recovery: their neurons returned to normal size and firing patterns.
"This study is a big breakthrough for the field of Alzheimer's research," said Yadong Huang, MD, PhD, associate director of the Gladstone Institute of Neurological Disease and senior author. "It opens the door to a better understanding of how APOE4 alters the function of neurons at a young age to increase risk of cognitive decline, and to the development of therapies that could block the detrimental effects of APOE4 early on."
The study also revealed that while most APOE4 is produced by astrocytes—supportive brain cells—the link between APOE4 and hippocampal hyperactivity depends entirely on neuron-produced APOE4. "When we deleted the APOE4 gene from astrocytes, nothing changed," said Zilberter. "But when we deleted it from neurons, the cells became larger and started functioning normally again." Further analysis showed high levels of Nell2 specifically in affected neurons; reducing Nell2 made these neurons less excitable.
Huang said Nell2 had not previously been studied alongside APOE4 but was known to be elevated in brains from Alzheimer’s patients with poor cognitive function. "What's exciting about Nell2 is that we were able to reverse the disease manifestations in adult mice by lowering its level," Huang said. "That tells us the damage is not irreversible, and that there may be a window for intervention even after disease processes have been triggered."
